Is there a need for combination therapy? No. Maria Buti Hospital General Universitario Valle Hebron Barcelona. Spain

Transcription

1 Is there a need for combination therapy? No Maria Buti Hospital General Universitario Valle Hebron Barcelona. Spain

2 No, No and No

3 EASL Update HBV Guidelines 2012 The most potent drugs with the optimal resistance profile should be used as first-line monotherapies Interferon Pegylated alfa 2a Tenofovir Entecavir Easl Guidelines. J hepatol 2012

4 Potential Advantage of Combination therapy

5 Undetectable* HBV DNA in HBV Patients After 1 Year of Treatment Undetectable* HBV DNA (%) Not head-to-head trials; different patient populations and trial designs HBeAg Positive LAM ADV TBV ETV 76 TDF 25 Peg- IFN HBeAg Negative LAM ADV TBV ETV 93 TDF 63 Peg- IFN *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45: Lok AS, et al. Hepatology. 2009;50:

6 Proportion of patients with HBV DNA <400 copies/ml at Year 5 with TDF HBeAg-ve: Week 240: TDF-TDF 83% On treatment analysis (missing = excluded): TDF-TDF = 99% HBeAg+ve: Week 240: TDF-TDF 64% On treatment analysis (missing = excluded): TDF-TDF = 96%, 1. Adapted from Marcellin P, et al. AASLD 2011; Oral #238.

7 Peg IFN -2a in HBeAg- CHB HBV DNA Levels Over Time 7 On-treatment Follow-up Mean HBV DNA (log 10 c/ml) Peg IFN 2a + placebo (n=177) Peg IFN 2a + LAM (n= 179) LAM (n= 181) 1 0 Marcellin et al. NEJM 2004;351: Study week

8 HBeAg Seroconversion in HBeAg-Positive Patients after 1 year Not head-to-head trials; different patient populations and trial designs HBeAg Seroconversion (%) ETV TDF PEGIFN PEGIFN+LMV ETV+TDF Entecavir Tenofovir Peginterferon *With sustained undetectable HBV DNA. Chang TT, et al. J Viral Hepat. 2009;16: Chang TT, et al. AASLD Abstract 109. Lau GK, et al. N Engl J Med. 2005;352: Marcellin P, et al. N Engl J Med. 2008;359: Buster EH, et al. Gastroenterology. 2008;135; Heathcote J, et al. AASLD Abstract 158. Heathcote J, et al. AASLD Abstract 483. Janssen HL, et al. Lancet. 2005;365; Lok A et al. Gastroenterol 2012;143:

9 HBsAg Loss Over Time in HBeAg-Positive Patients Not head-to-head trials; different patient populations and trial designs Nucleos(t)ide Analogues vs Peginterferon vs Combination therapy 1 year results 100 HBsAg Loss (%) Monotherapy PeGIFN+LMV ETV+TDF *With sustained undetectable HBV DNA. Entecavir Tenofovir Peginterferon Chang TT, et al. N Engl J Med. 2006;354: Marcellin P, et al. N Engl J Med. 2008;359: Buster EH, et al. Gastroenterology. 2008;135; Gish R, et al. Gastroenterology. 2007;133: Heathcote J. AASLD Abstract 158. Heathcote J, et al. AASLD Abstract 483. Janssen HL, et al. Lancet. 2005;365: Lok A, et al Gastroenterology 2012

10 Suppression of HBV-DNA does not correlate with the induction of immune control An argument against combination

11 Potential Advantage of Combination therapy

12 Resistance rates through 6 years among nucleos(t)ide-naïve patients Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 72 Weeks LVD 1 23% 46% 55% 71% 80% ADV 1 0% 3% 11% 18% 29% LdT 2,3 5% 25% TDF 4 0% 0% 0% 0% 0% 0% ETV* 5,6 <1% <1% 1.2% 1.2% 1.2% 1.2% These trials used different populations, exclusion criteria, follow-up end points, and they were not head-to-head comparisons for all the drugs * Cumulative probabilities of resistance taken; Naïve HBeAg (+) ; Naïve HBeAg(-); N/A not available 1. Locarnini S. Hepatol Int. 2008;2: Lai CL, et al. N Engl J Med, 2007;357:2576-8; 3. Liaw YF, et al. Gastroenterology 2009;136: Snow- Lampart A, et al. AASLD Oct 31 Nov 4, 2008, San Francisco, USA. Oral Presentation 977 Hepatology 2008;48:745A. 5. Baraclude EU SmPC, February Tenney et al. EASL April 22 26, 2009, Copenhagen, Denmark, Oral Presentation 1761.

13 No resistance with Tenofovir and minimal with Entecavir An argument more against combination

14 Potential Advantage of Combination therapy

15 Treatment-naïve patients TDF treatment in patients with liver cirrhosis (studies ) % of patients with HBV DNA <400 c/ml Percentage (%) HBV DNA <40 copies/ml Weeks on study Cirrhotic N= Non-Cirrhotic N= Buti, et al., EASL 2009; Abstract 21.

16 Tenofovir vs. Entecavir vs. Truvada in Decompensated Chronic Hepatitis B Liver Disease HBV DNA < 400 Copies/mL (69 IU/mL): ITT Percentage % TDF TVD ETV Week 12 Week 24 Week 48 TDF (N=45) TVD (N=45) ETV (N=22) Median CPT score (Q1, Q3) Baseline Mean Change week 48 7 (6-8) -1 7 (6-9) -1 7 (6-8) -1 Liaw YF et al. Hepatology 2010

17 Entecavir Monotherapy vs Entecavir + Tenofovir Combination for NA-Naive HBV BE-LOW: open-label, randomized, multicenter, phase IIIb study No overall benefit of combination therapy vs monotherapy No difference in seroconversion rates Combination may benefit HBeAg-positive patients with high HBV DNA HBV DNA < 50 IU/mL (%) HBV DNA < 50 IU/mL at Wk 96: By HBeAg Status n/n = 0 P = / 111/ HBeAg+ Noncompleter = failure / 56 53/ 59 HBeAg- Lok A, et al. Gastroenterology 2012 ETV ETV + TDF HBV DNA < 50 IU/mL at Wk 96 in HBeAg+ Patients: By Baseline HBV DNA / 111/ n/n = All HBeAg / / 53 BL HBV DNA < 10 8 IU/mL Difference 16.8% (95% CI: ) 62 49/ / 85 BL HBV DNA 10 8 IU/mL ETV ETV + TDF

18 Partial virological response with Entecavir 100 Partial virological response at week 48 occurred in 36/243 NA-naïve patients <1000 IU/mL 80 % Cumulated response IU/mL Number of patients without response Treatment week <1000 IU/mL at week IU/mL at week a Total number of patients in follow up a Three patients were switched to TDF+emtricitabine and one patient received TDF add-on therapy Zoutendijk et al. Hepatology 2011

19 The addition of FTC to TDF from Weeks did not impact subsequent HBV DNA decline All subjects analysed with >400 copies/ml had no evidence of TDF resistance 1. Marcellin P, et al. AASLD 2011; Oral #238. Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV

20 TDF alone or with FTC in LAM-treated patients 8 7 LAM Res TDF (n=7) Treatment LAM Res FTC/TDF (n=7) Mean HBV DNA (log 10 copies/ml) NOT LAM Res TDF (n=46) NOT LAM Res FTC/TDF (n=46) Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV 2 LLOQ Weeks on study Berg T, et al. AASLD 2010; Oral #136.

21 Therapy of Drug Resistance EASL Guidelines 2012 LAM resistance: switch to TDF (add ADV if TDF not available) ADV resistance: in NUC-naive patients before ADV, switch to ETV or TDF in patients with prior LAM resistance, switch to TDF and add a nucleoside analogue (LAM, TBV, ETV, FTC) TBV resistance: switch to or add TDF (add ADV if TDF not available) ETV resistance: switch to or add TDF (add ADV if TDF not available) MDR resistance: combination of ETV and TDF or combination of FTC and TDF

22 No advantage in difficult to treat poulations An argument more against combination

23 Potential Disadvantage of Combination therapy

24 Telbivudine SmPC: special warnings and precautions for use Special warning/precaution Risk of myopathy and myalgia 1 0.3% (10/3.500 in monotherapy) Increased risk of peripheral neuropathy when telbivudine and pegylated interferon alfa-2a are co-administered 11% (4/28) on combo Implication/monitoring Implications for co-administration with other medicines associated with myopathy (e.g. statins, fibrates, cyclosporins) Late onset median 14 mo Monitor patients carefully for signs of peripheral neuropathy and reconsider treatment options if suspected that patient developing peripheral neuropathy Early onset median 4.5 mo Lower likelihood of improvement Sebivo (telbivudine) SmPC, March 2010.

25 Potential Disadvantages of Combination therapy

26 Average Cost per -yr Treatment in Spain

27 Type of Combination

28 CONCLUSIONS With the current medication, there is no need of CT except for HIV-HBV coinfected patients, and patient with MDR strains BUTI, in the future, with new drugs with different mechanisms of action, combination therapy could be an option.

29 Mies Van der Rohe Lessismore German Pavillon Barcelona Neus National Galerie Berlin